Liquid pharmaceutical composition

ABSTRACT

This invention relates to new pharmaceutical compositions and methods for their preparation, and in particular it relates to taste-masked liquid compositions comprising a solution of a histamine H 2 -antagonist complexed with an alginate and also containing a humectant. The solution is buffered to a pH of between about 6 to 7. The inventive solution may be flavored and sweetened and preserved.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to new pharmaceutical compositions and methodsfor their preparation, and in particular it relates to taste-maskedliquid compositions comprising a solution of a histamine H₂-antagonistcomplexed with an alginate.

2. Description of Related Art

The histamine H₂-receptor antagonists are a highly successful class ofdrugs. These compounds are widely prescribed to treat gastrointestinaldisorders and are usually administered orally. Unfortunately, mostmembers of this class have the drawback of having an extremelydisagreeable taste. The art has recognized this problem and has appliedmany different approaches to trying to solve this problem.

U.S. Pat. No. 4,996,222 describes a pharmaceutical suspension ofcimetidine having a pH of at least 7 wherein substantially all of thecimetidine is in the polymorph B crystalline form. The composition willcontain a suspending agent. The composition may contain alginate as athickening agent. Examples of suspending agents include xanthan gum,hydroxypropylmethylcellulose, methylcellulose, carageenan, sodiumcarboxymethyl cellulose, and sodium carboxymethylcellulose/microcrystalline cellulose mixtures, particularly sodiumcarboxymethyl cellulose/microcrystalline cellulose mixtures.

Thus, in U.S. Pat. No. 5,576,344,a process for reducing the adversetaste and malodor associated with H₂-receptor antagonist nizatidine isdescribed. The process involves forming an aqueous solution of thecompound and subjecting the solution to elevated temperatures sufficientfor a period sufficient to cause a reduction in the adverse taste and/ormalodor.

U.S. Pat. No. 5,622,980 describes a solid composition for oraladministration of an H₂-receptor antagonist which composition includes asilicate taste-masking agent capable of forming an adsorbate complexwith the H₂-antagonist wherein the complex exhibits a non-bitter taste.The complex inhibits the release of the H₂-antagonist in the oralcavity.

Chewable tablets containing unpleasant tasting medicaments such ascimetidine are disclosed in U.S. Pat. No. 5,275,823. The palatability ofthe tablets is improved by including certain hygroscopic water-insolublesubstances as extragranular excipients. Such excipients includecellulose derivatives, sodium starch glycolate and cross-linkedpolyvinylpyrrolidine.

A chewable dosage form containing a histamine H₂-receptor antagonist inan amount which is effective to treat a gastrointestinal disorder isprovided in a palatably acceptable form in U.S. Pat. No. 6,270,807. Thedosage form comprises granules containing the histamine H2-receptorantagonist, which are provided with a taste-masking coating comprising awater-insoluble, water-permeable methacrylate ester copolymer in whichthe coating is applied to the granules in an amount which provides ataste-masking effect for a relatively short period during which thecomposition is being chewed by a patient, but which allows substantiallyimmediate release of the histamine H₂-receptor antagonist after thecomposition has been chewed and ingested.

U.S. Pat. No. 6,197,348 discloses a taste-masked pharmaceuticalcomposition. There is provided a taste masked oral pharmaceuticalcomposition including: a pharmaceutically active ingredient having apH-dependent solubility; a polymer encapsulating said pharmaceuticallyactive ingredient, said polymer having a quaternary ammoniumfunctionality; a suspending medium for suspending the encapsulatedpharmaceutically active ingredient, said medium adjusted to apredetermined pH at which the pharmaceutically active ingredient remainssubstantially insoluble; and wherein the pharmaceutically activeingredient is taste masked by the combination of the polymer andsuspending medium.

Taste masked immediate release micromatrix powders are described in U.S.Pat. No. 6,153,220. Taste masked immediate release micromatrix powderscan be formed by spray drying the drug and cationic copolymer whereassustained release micromatrix powders can be formed by granulatingcontrolled release powders, which can be made by spray drying the drugwith a retarding polymer, with the cationic copolymer. These powderscontaining drugs with poor organoleptic properties can be incorporatedinto conventional oral dosage forms such as sprinkles, suspension, fastmelt tablets, chewable tablets or effervescent tablets.

BRIEF SUMMARY OF THE INVENTION

This invention relates to new pharmaceutical compositions and methodsfor their preparation, and in particular it relates to taste-maskedliquid compositions comprising a solution of a histamine H₂-antagonistcomplexed with an alginate and also containing a humectant. The solutionis buffered to a pH of between about 6 to 7. The inventive solution maybe flavored and sweetened and preserved.

DETAILED DESCRIPTION OF THE INVENTION

Histamine H₂-antagonists have been used for a number of years in thetreatment of duodenal and benign gastric ulceration, recurrent andstomal ulceration, esophageal reflux disease and other conditions wherereduction of gastric acid has been shown to be beneficial, for examplepersistent dyspeptic symptoms with or without ulceration. The members ofthis class of medicines have a very bitter taste and palatability oforal compositions is a major consideration and has been a major problemin the preparation of liquid oral compositions. Although the inclusionof a bitter tasting medicine in a coated tablet or within a capsuleovercomes the problem of offensive taste, many adults and many childrenthat have difficulty swallowing tablets or capsules cannot benefit fromthese dosage forms.

Solutions of histamine H₂-antagonists have been found to be unpalatable.We have found that by preparing a solution of H₂-antagonists with analginate, a taste-masked composition is formed. The taste-masking isbelieved to result a complex being formed between the H₂-antagonist andthe alginate. The taste masking effect is augmented by the addition ofsweetener, flavor, artificial sweetener enhancer and a humectant.

It is clear that there has been a need for compositions of histamine H₂antagonists which are liquid based and are palatable. HistamineH₂-antagonists are believed to be absorbed almost exclusively in thesmall intestine and liquid-based compositions offer the possibility thatthey could be absorbed more quickly and more efficiently than tabletcompositions, particularly tablet compositions which have been coated tominimize unpleasant tastes.

The composition of the present invention can be prepared by mixing analginate dispersion in a humectant and preservative solution with abuffered solution of histamine H₂ antagonist then adding the sweetener,artificial sweetener enhancer (optional) and flavor then adjusting thepH to about 6.5±0.5 and adding sufficient purified water to bring thesolution to its final volume.

Examples of sweeteners include:

A. Water-soluble sweetening agents such as monosaccharides,disaccharides and polysaccharides such as xylose, ribose, glucose,mannose, galactose, fructose, dextrose, sucrose, sugar, maltose,partially hydrolyzed starch, or corn syrup solids and sugar alcoholssuch as sorbitol, xylitol, mannitol and mixtures thereof.

B. Water-soluble artificial sweeteners such as the soluble saccharinsalts, i.e., sodium, or calcium saccharin salts, cyclamate salts,acesulfam-K, ammonium glycyrrhizinate, dipotassium glycyrrhizinate andthe like, and the free acid form of saccharin.

C. Dipeptide based sweeteners such as L-aspartylphenylalanine methylester and materials described in U.S. Pat. No. 3,492,131 and the like.

A water soluble sweetener (A.) will usually be present in an amountcorresponding to about 20 to 50% w/v of the total composition, theamount depending in part upon whether other sweetener ingredients arepresent and the level of sweetness desired.

When sugar is used as the sweetener, typically it is present from about20% to about 50% w/v of the composition. It will be appreciated thatcombinations of sweeteners can be used.

The sweetening agents when used, may also be used alone or incombination with each other.

Humectants such as glycerol and propylene glycol are present in thecomposition. Typically the total quantity of humectant present is in therange of about 8 to 15% w/v. Thus, for example, propylene glycol andglycerol can each be present individually or in combination.

An artificial sweetness enhancer may optionally be utilized in thepresent invention. When an artificial sweetness enhancer is utilized, itmay be present in an amount from about 0.05% to about 1.5% w/v of thefinal composition. Preferably, the artificial sweetness enhancer will bepresent in an amount from about 0.1% to about 1% w/v of the finalcomposition. Typical artificial sweetness enhancer would be Pro Sweet®manufactured by the Virginia Dare company and Sweet AM® from Flavors ofNorth America.

It is preferred that the liquid compositions of the present inventioncontain preservatives to prevent microbial contamination. Examples ofpreservatives are the alkylparabens, particularly methylparaben,propylparaben and butylparaben. The amount of preservative generallyutilized will vary depending upon the preservative selected and may forexample range from about 0.05% to about 1.5% w/v of the finalcomposition. Preferably, the preservative will be present in an amountfrom about 0.01% to about 0.1% w/v of the final composition.

Suitable flavorings include both natural and artificial flavors, andmints such as peppermint, menthol, artificial vanilla, cinnamon, variousfruit flavors, both individual and mixed, and the like are contemplated.The flavorings are generally utilized in amounts that will varydepending upon the individual flavor, and may, for example, range inamounts of about 0.01% to about 1% by weight/volume of the finalcomposition. Preferably, the flavorants will be present in an amount ofabout 0.01% to about 0.1% w/v of the final composition. The flavorantsinclude synthetic flavorants or natural flavorants, such as lemon, lime,orange, menthol, strawberry, bubblegum, and the like.

The optional colorants useful in the present invention, include thepigments such as titanium dioxide, that may be incorporated in amountsof up to about 1% by weight/volume, and preferably up to about 0.6% byweight/volume. Also, the colorants may include other dies suitable forfood, drug and cosmetic applications, and known as F.D. & C. dyes andthe like. The materials acceptable for the foregoing spectrum of use arepreferably water-soluble. Illustrative examples include indigoid die,known as F.D. & C. Blue No. 2, which is the disodium salt of5,5′-indigotindisulfonic acid. Similarly, the dye known as F.D. & C.Green No. 1, comprises a triphenylmethane dye and is the monosodium saltof4-[4-Nethyl-p-sulfobenzylamino)diphenylmethylene]-[1-(N-ethyl-N-p-sulfoniumbenzyl)-2,5-cyclohexadienimine].A full recitation of all F.D. & C. and D. & C. and their correspondingchemical structures may be found in the Kirk Othmer Encyclopedia ofChemical Technology, in Volume 5, at Pages 857-884, which text isaccordingly incorporated herein by reference.

The liquid compositions of the present invention may optionally containingredients which improve its taste, such as sodium chloride and naturaland artificial flavour enhancers such as monosodium glutamate, soy sauceand the like.

The liquid compositions of the present invention contain from about 0.5to 5% w/v histamine H₂-antagonist. Preferably, the histamineH₂-antagonist will be present in an amount of about 0.01% to about 0.1%w/v of the final composition. The histamine H₂ antagonist is selectedfrom the group consisting of nizatidine, famotidine, ranitidine, andcimetidine.

The ratio of histamine H₂-antagonist to alginate is about 1:0.1 to about1:0.6 w/w and preferably about 1:02 to about 1:04 w/w.

Alginates are a hydrophilic, colloidal polysaccharide in the form ofsalts such as sodium, calcium, magnesium and other bases. The preferredform of alginate is an alkali metal salt most preferably the sodiumsalt. Alginate is present in an amount of about 20% to about 40% w/w ofthe histamine H₂-antagonist.

Buffers: The buffer comprises acids and their base salts for example,citric acid (e.g., citric acid anhydrous), tartaric acid, malic acid,phosphoric acid and the like and their respective salts.

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings and the inventionis not limited to the example herein. It is therefore understood thatwithin the scope of the appended claims, the invention may be practicedotherwise than as specifically described herein.

In one preferred embodiment of the invention there is provided acomposition containing 0.5 to 2.5% w/v of histamine H₂-antagonist. Inanother preferred embodiment, the histamine H₂-antagonist is nizatidine.

EXAMPLE

A sample nizatidine formulation: Component per 100 ml. % w/v Nizatidine0.5 to 2.5 Humectant  8 to 15 Sodium alginate 0.1 to 1.5 Sodium chloride0.1 to 0.5 Artificial sweetener 0.1 to 0.5 Buffer 0.5 to 1.5Preservative 0.05 to 0.5  Natural sweetener 20 to 50 Flavor 0.01 to 1.0 Artificial sweetness enhancer 0.1 to 0.9 Water to 100% v/v QSProcessPremix 1:

Add with mixing the preservative(s) to the humectant which is containedin a suitable vessel and has been preheated to about 60° C.±5° C. andcontinue mixing until dissolved. Cool the solution to about 50° C.±5° C.then slowly add the alginate with continued mixing to uniformly dispersethe alginate in the liquid.

In a second vessel, add an amount of purified water equal to about 64%of the final batch volume. Add the following ingredients in the orderlisted below, with continuous mixing and not adding the next ingredientuntil the current added ingredient is completely dissolved.

-   -   1. Flavor enhancer (salt)    -   2. Artificial sweetener    -   3. Buffering agent (basic portion first if a two component        buffer)    -   4. Buffering agent (acidic portion if applicable)    -   5. Histamine H sub 2 antagonist    -   6. Premix 1    -   7. Sweetener    -   8. Artificial sweetener enhancer    -   9. Flavor    -   10. EDTA (optional)        Stop mixing and pre qs to 95% of the final batch volume then mix        until the solution is uniform. Measure the pH (use temperature        compensation to RT) and adjust the pH if necessary to 6.5. If        the pH is greater than 6.5, adjust by adding citric acid        solution 20% and mix well. If the pH is less than 6.5, adjust by        adding sodium hydroxide 1N and mix well. Discontinue mixing and        qs to the final batch volume with purified water.

1. A liquid pharmaceutical composition for the oral administration of atherapeutically effective amount of nizatidine, said compositioncomprising a solution of nizatidine or a pharmaceutically acceptablesalt thereof and a taste-masking agent capable of forming a complex withthe nizatidine wherein said taste-masking agent comprises alginate andwherein said composition exhibits a non-bitter taste.
 2. Thepharmaceutical composition according to claim 1, wherein the alginatetaste-masking agent comprises sodium alginate.
 3. The pharmaceuticalcomposition according to claim 1, wherein the nizatidine is in the formof a pharmaceutically acceptable salt.
 4. The pharmaceutical compositionaccording to claim 1, wherein the nizatidine is in the form of a freebase.
 5. The pharmaceutical composition according to claim 1, whereinthe ratio of nizatidine to alginate taste-masking agent is from 1:0.1 to1:0.6 weight:weight.
 6. The pharmaceutical composition according toclaim 1, wherein the ratio of nizatidine to alginate is about 1:0.2 toabout 1:0.4 weight:weight.
 7. The pharmaceutical composition accordingto claim 1 further comprising a flavoring agent selected from the groupsconsisting of natural and artificial flavors and mints.
 8. Thepharmaceutical composition according to claim 1 further comprising asweetening agent selected from the group consisting of water-solublesweetening agents, water-soluble artificial sweetening agents andmixtures thereof.
 9. The pharmaceutical composition according to claim8, wherein said water-soluble natural sweetening agent is selected fromthe group consisting of: xylose, ribose, glucose, mannose, galactose,fructose, dextrose, sucrose, sugar, maltose, partially hydrolyzedstarch, corn syrup solids, sorbitol, xylitol, mannitol and mixturesthereof.
 10. The pharmaceutical composition according to claim 8,wherein said artificial sweetening agent is L-aspartylphenylalaninemethyl ester.
 11. The pharmaceutical composition according to claim 8,wherein said water-soluble artificial sweetening agent is selected fromthe group consisting of: sodium or calcium saccharin salts, cyclamatesalts, acesulfam-K, ammonium glycyrrhizinate, dipotassiumglycyrrhizinate, and the free acid form of saccharin.
 12. Thepharmaceutical composition according to claim 7, wherein said flavoringagent is present in from about 0.01% to about 1% by weight/volume of thefinal composition.
 13. The pharmaceutical composition according to claim7, wherein said flavoring agent is one or more members selected from thegroup consisting of: peppermint, menthol, artificial vanilla, cinnamon,lemon, lime, orange, menthol, strawberry, bubblegum, and mixturesthereof.
 14. The pharmaceutical composition according to claim 1,further comprising a humectant.
 15. The pharmaceutical compositionaccording to claim 14, wherein the humectant is present in an amountfrom 8 to 15 percent w/v of the final composition.
 16. Thepharmaceutical composition according to claim 14, wherein the humectantis selected from the group consisting of glycerol, propylene glycol andmixtures thereof.
 17. The pharmaceutical composition according to claim1, wherein the liquid is adjusted to a pH of 6.0 to 7.0.
 18. Thepharmaceutical composition according to claim 1, wherein the liquid isadjusted to a pH of 6.0 to 6.9.
 19. The pharmaceutical compositionaccording to claim 1, wherein the liquid is adjusted to a pH of 6.25 to6.75.
 20. The pharmaceutical composition according to claim 1, furthercomprising an artificial sweetness enhancer in from about 0.05 to about1.5 percent w/v of the final composition.
 21. The pharmaceuticalcomposition according to claim 1, further comprising EDTA in an amountfrom about 0.05% w/v to about 0.1% w/v.